Lower urinary tract disorders, including overactive bladder, detrusor instability, and urinary incontinence can arise from numerous pathologies. These pathologies are commonly classified as neuropathic, myogenic, or idiopathic. The majority of patients usually are characterized as idiopathic due to the lack of observable disease etiology.
Recent studies (Kim, et al., Urology, 65(2):238-42 (2005); Kim, et al., BJU Int'l, 97(2):400-03 (2005)) have suggested the sensory system of the urothelium may play an important role in afferent signaling and detrusor activity. Pathologies of this system have been suggested to play a significant role in many patients with lower urinary tract idiopathic disease.
Standard drug therapies for patients with idiopathic lower urinary tract disorders are systemic treatments typically administered orally or trans-dermally. These therapies often lack adequate efficacy due to either dose limiting side effects, low potency, or both.
Currently patients failing systemic drug therapy have only two alternatives. The first alternative is Botox injections directly into the bladder wall, which may provide symptom relief, but which also undesirably can produce prolonged urinary retention requiring self-catheterization. The second alternative is neurosacral stimulation as produced by the InterStim® device which is surgically implanted and shown to provide symptomatic relief. However, the equipment and surgical procedure is expensive, highly invasive, and carries a 30% adverse event rate requiring corrective surgeries or removals.
Recent studies have suggested that intravesical administration of anti-muscarinic agents produces a different pharmacological response compared to systemic therapy (Kim, et al., Urology, 65(2):238-42 (2005); Kim, et al., BJU Int'l, 97(2):400-03 (2005)). These results have been primarily based on animal studies in which muscarinic agonists, for example carbachol, are used to stimulate urothelial activity to mimic sensory dysfunction.
In one of these studies (Kim, et al. Urology, 65(2):238-42 (2005)), antimuscarinic agents were instilled intravesically in two protocols—high dose and low dose. For the high dose (167 μg/mL) protocol, 300 μM atropine sulfate, 420 μM oxybutynin chloride, 410 μM dimethindene maleate were administered. These doses, except for dimethindene, were based on reported clinical trials that intravesically instilled these agents. Dimethindene was used for experimental purposes only. For the low dose (0.1 and 0.5 μg/mL) protocol, dimethindene, oxybutynin, tolterodine, and trospium were administered. These doses—0.1 and 0.5 μg/mL—were based on the excreted urine concentration of trospium in humans after receiving a steady-state oral dose of 40 mg/24 hours.
Based on carbachol antagonism (carbachol 30 μM (M1, M2, M3, AChRa2 agonist)), this study suggested that there are no significant differences among antimuscarinics when administered intravesically despite differences in chemical structure, muscarinic receptor selectivity, and potency. Within the low dose protocol, the intercontraction interval ratio to baseline data revealed that dimethindene, oxybutynin, tolterodine, and trospium all performed similarly.
In a related study (Kim, et al., BJU Int'l, 97(2):400-03 (2005)), human volunteers collected urine after taking oral therapeutic doses of trospium (20 mg, twice daily), tolterodine LA (4 mg, once daily), or oxybutynin XL (10 mg, once daily) for 5 days. The human urine was then infused into the bladders of rats to test the effects of antimuscarinics excreted into the urine on normal bladder activity. Although the data indicated that trospium had a more positive effect on bladder capacity and intercontraction interval than oxybutynin and tolterodine, this discrepancy was caused by the fact that 60-80% of the active parent compound of trospium chloride was excreted in the human's urine while <5% of the active compound of oxybutynin or tolterodine was excreted in the human's urine.
The urothelial sensory system is comprised of numerous receptors and signaling pathways, many of which exhibit significant “cross talk.” Due to the complexity of the urothelial sensory system, selective agents, such as darifenasin, may not adequately modulate urothelial sensory activation following nonspecific noxious stimuli. Similarly, non-specific agents, such as oxybutynin which exhibits antimuscarinic and calcium channel activity, do not inhibit urothelial response as measured by intercontraction intervals but can lead to urinary retention.
Accordingly, there remains a need for more and better treatment options for lower urinary tract disorders, including overactive bladder, detrusor instability, and urinary incontinence. Desirably, such treatments would address one or more of the problems associated with systemic administration of drugs and with highly invasive and expensive surgical procedures. Desirably, the treatment would also avoid or lessen the need for painful injections and repeated self-catheterization.